Journal of Clinical Endocrinology & Metabolism最新文献

Context: Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable antitumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128).

Methods: We describe the first 6 pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study.

Results: Of the 6 patients (1 sporadic and 5 reported as part of MEN2 syndromes) in this case report, 4 had a partial response/complete response and 2 had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications.

Conclusion: These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition.

Background: This research aims to investigate the connection between systemic inflammatory response and metabolic syndrome (MetS) across different age groups, with the aim of proposing more targeted recommendations.

Methods: This study enrolled 15 959 adults from the 2001-2018 National Health and Nutrition Examination Survey of whom 6739 were diagnosed with MetS. After dividing the systemic immune-inflammation index (SII) into 4 quartiles, the Kruskal-Wallis test and weighted chi-square test were employed to assess statistical differences. Weighted multivariable logistic regression analysis, subgroup analysis, sensitivity analysis, and restricted cubic spline were employed to examine the relationship between SII and MetS.

Results: Our study revealed that SII exhibits a quantitative association with MetS [odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.37-1.79; P < .001]. Elevated SII is an independent risk factor for the 5 components of MetS. Different age groups and alcohol consumption status could modify the connection between SII and MetS. This connection was statistically significant in the 18 to 65 age group but not in the elderly subgroup (OR = 1.08; 95% CI, .95-1.23; P = .248). Multiple imputation confirmed the robustness of our results. Moreover, the connection exhibits an inverted U-shaped curve.

Conclusion: Our research highlights the predictive significance of SII in forecasting the incidence of MetS in young and middle-aged populations. The differences in inflammatory mechanisms across various age groups necessitate further research for exploration.

Context: Exercise reduces adiposity, but its influence on bone marrow fat fraction (BMFF) is unknown; nor is it known whether a reduction in liver fat content mediates this reduction.

Objectives: This work aimed to determine whether incorporating exercise into a lifestyle program reduces the lumbar spine (LS) BMFF and to investigate whether changes in liver fat mediate any such effect.

Methods: Ancillary analysis of a 2-arm, parallel, nonrandomized clinical trial was conducted at primary care centers in Vitoria-Gasteiz, Spain. A total of 116 children with overweight/obesity were assigned to a 22-week family-based lifestyle program (control group [n = 57]) or the same program plus an exercise intervention (exercise group [n = 59]). The compared interventions consisted of a family-based lifestyle program (two 90-minute sessions/month) and the same program plus supervised exercise (three 90-minute sessions/week). The primary outcome examined was the change in LS-BMFF between baseline and 22 weeks, as estimated by magnetic resonance imaging. The effect of changes in hepatic fat on LS-BMFF were also recorded.

Results: Mean weight loss difference between groups was 1.4 ± 0.5 kg in favor of the exercise group. Only the children in the exercise group experienced a reduction in LS-BMFF (effect size [Cohen d] -0.42; CI, -0.86 to -0.01). Importantly, 40.9% of the reductions in LS-BMFF were mediated by changes in percentage hepatic fat (indirect effect: β=-0.104; 95% CI, -0.213 to -0.019). The effect of changes in hepatic fat on LS-BMFF was independent of weight loss.

Conclusion: The addition of exercise to a family-based lifestyle program designed to reduce cardiometabolic risk improves bone health by reducing LS-BMFF in children with overweight or obesity. This beneficial effect on bone marrow appears to be mediated by reductions in liver fat.

Context: Carney complex (CNC) is a familial neoplasia syndrome associated with GH excess (GHE).

Objective: To describe the frequency of GHE in a large cohort of patients with CNC and to identify genotype-phenotype correlations.

Methods: Patients with CNC with at least 1 biochemical evaluation of GH secretion at our center from 1995 to 2021 (n = 140) were included in the study. Diagnosis of GHE was based on levels of IGF-1, GH suppression during oral glucose tolerance test, GH stimulation after thyrotropin administration and overnight GH secretion.

Results: Fifty patients (35.7%) had GHE, and 28 subjects (20%) had symptomatic acromegaly, with median age at diagnosis of 25.3 and 26.1 years, respectively. Most of the patients (99.3%) had a PRKAR1A gene defect. There was a higher risk of GHE in patients harboring a variant that led to no expression of the affected allele [hazard risk (HR): 3.06, 95% confidence interval (CI): 1.2-7.8] and for patients harboring the hotspot variant c.491_492delTG (HR: 2.10, 95% CI: 1.1-4.1). Almost half of patients with CNC had an abnormal finding on pituitary imaging. CNC patients with abnormal pituitary imaging had a higher risk of GHE (HR: 2.94, 95% CI: 1.5-5.8), especially when single or multiple adenoma-like lesions were identified. Management of patients with symptomatic acromegaly involved surgical and medical approaches.

Conclusion: Dysregulation of GH secretion is a common finding in CNC. Knowing the clinical spectrum of this disorder and its association with genetic and imaging characteristics of the patient make more likely its prompt diagnosis and better management.

Most disorders of steroidogenesis, such as forms of congenital adrenal hyperplasia (CAH) are caused by mutations in genes encoding the steroidogenic enzymes and are often recognized clinically by cortisol deficiency, hyper- or hypo-androgenism, and/or altered mineralocorticoid function. Most steroidogenic enzymes are forms of cytochrome P450. Most P450s, including several steroidogenic enzymes, are microsomal, requiring electron donation by P450 oxidoreductase (POR); however, several steroidogenic enzymes are mitochondrial P450s, requiring electron donation via ferredoxin reductase (FDXR) and ferredoxin (FDX). POR deficiency is a rare but well-described form of CAH characterized by impaired activity of 21-hydroxylase (P450c21, CYP21A2) and 17-hydroxylase/17,20-lyase (P450c17, CYP17A1); more severely affected individuals also have the Antley-Bixler skeletal malformation syndrome and disordered genital development in both sexes, and hence is easily recognized. The 17,20-lyase activity of P450c17 requires both POR and cytochrome b5 (b5), which promote electron transfer. Mutations of POR, b5, or P450c17 can cause selective 17,20-lyase deficiency. In addition to providing electrons to mitochondrial P450s, FDX, and FDXR are required for the synthesis of iron-sulfur clusters, which are used by many enzymes. Recent work has identified FDXR mutations in patients with visual impairment, optic atrophy, neuropathic hearing loss, and developmental delay, resembling the global neurologic disorders seen with mitochondrial diseases. Many of these patients have had life-threatening events or deadly infections, often without an apparent triggering event. Adrenal insufficiency has been predicted in such individuals but has only been documented recently. Neurologists, neonatologists, and geneticists should seek endocrine assistance in evaluating and treating patients with mutations in FDXR.

Context: Cosmetic paraffin oil injections can lead to granuloma formation, causing hypercalcemia and kidney failure.

Objective: This study explores whether debulking surgery is an effective treatment for improving calcium homeostasis, inflammation, and clinical symptoms.

Methods: In a retrospective study, we reviewed 33 patients undergoing debulking surgery. Changes in calcium, inflammatory markers, and renal function from baseline up to 12 months after surgery were assessed. Patients were interviewed after surgery.

Results: The patients were 34.6 years of age (SD 6.9) and had 1104 grams (SD 591) of granuloma tissue removed following injection of 1329 mL (SD 803) paraffin oil 7.9 years (SD 3.2) earlier. Seventeen patients had hypercalcemia and experienced a significant decline in ionized calcium from 1.48 mmol/L (SD 0.16) at baseline to 1.33 mmol/L (SD 0.03) at 12 months (P < .002), although only 4 men (23.5%) became normocalcemic. Serum ferritin was reduced by 50% after 12 months (P = .048). Sixteen patients were normocalcemic and had no change in calcium homeostasis but experienced a 20% drop in serum ferritin levels (P = .025) after surgery. Fifteen patients completed all their planned surgeries within the study period and experienced a decline in serum ionized calcium (P = .031), ferritin (P = .011), and interleukin 2-receptor (P = .037). A survey showed that 55% of patients reported postoperative satisfaction scores of 10/10, and 59% of the patients reported reduced pain.

Conclusion: Surgery improved calcium homeostasis in a fraction of patients and reduced inflammation and subjective symptoms such as pain and mental well-being in a patient group left with few treatment options except high-dose prednisolone.

Context: Handgrip strength (HGS) is an important indicator of sarcopenia and adverse health outcomes. However, evaluating HGS in children presents challenges, and its association with metabolism remains incompletely understood.

Objective: To establish grip strength reference values for Chinese children and adolescents, as well as to evaluate the relationship between HGS and cardiometabolic risk.

Methods: Data were collected from 4 072 participants aged 6-18 as part of the Evaluation and Monitoring on School-based Nutrition and Growth in Shenzhen (EMSNGS) study. HGS was measured, and relative HGS (RHGS) was normalized by body mass index. Age- or weight-specific HGS and RHGS were derived using the generalized additive model of location, scale, and shape model, and participants' values were categorized into quartiles, defining low strength as the lowest quartile. The cardiometabolic risk index (CMRI) z-score was calculated, with high risk defined as a z-score of ≥1.

Results: Both boys and girls exhibited similar increases in age- and weight-specific grip strength. Low grip strength, classified by weight-specific HGS and RHGS, was linked to higher CMRI z-scores than classifications based on age-specific references in both sexes. A dose-dependent relationship was observed between weight-specific grip strength and cardiometabolic risk, particularly in boys. Compared with the middle category (P25th-P75th), the odds ratios for high cardiometabolic risks associated with low grip strength increased in both sexes.

Conclusion: This study established grip strength reference values for Chinese youth, introduced the concept of weight-specific HGS and RHGS, and demonstrated a dose-dependent relationship between weight-specific grip strength and cardiometabolic risk. These findings highlighted the association between low muscle strength and increased cardiometabolic risk.

Context: Genetic variation in SHBG structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration.

Objective: To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men.

Design, setting and participants: Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean, 34.5) years.

Main outcome measures: Genotyping using microarray (Illumina) for single-nucleotide polymorphism (SNPs) suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis.

Results: Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; P < .05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all P < .05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all P < .05). No clear effects on measured free T were found, except for a trend toward higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; P < .05) in the larger global study population.

Conclusion: In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.